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Hepatitis B: Epidemiology and Public Health Issues Perinatal Hepatitis B Prevention Program 2nd Bi-Annual State Conference May 11, 2010 Austin, Texas Gary Heseltine MD MPH Epidemiologist - Infectious Disease Control Unit Chronic Illnesses Demand Chronic Attention Topics • Hepatitis what is it? • Hepatitis B acute – Basic epidemiology, risks, transmission • Hepatitis B chronic – Disease burden and sequelae – A health disparity • Global burden of hepatitis B – Modes of transmission, including injection safety • Perinatal hepatitis B – Efficacy of prevention strategies • Patient safety culture and process improvement Liver • Located upper right side abdomen • Largest gland in body; 1.3 - 1.6kg • Receives most nutrients absorbed by GI tract • Essential role in metabolism of fats, sugars, and proteins • Produces bile, clotting substances, proteins, stores sugar • Detoxifies compounds • Processes old erythrocytes Hepatitis: Inflammation of the Liver • Disease process characterized by – diffuse inflammatory infiltrate – with or without necrosis and local fibrosis. • Clinical forms – Acute – Chronic - persistent infection/inflamation > 6 months • Etiology – Usually a virus sometimes a toxic or chemical substance, immunologic process • Origin: [hepat- + -itis] – G. hēpar- (liver) + G. -itis (f. form -ites) – -itis: usage now denotes inflammation Agents of Viral Hepatitis • Enteric transmission – Hepatitis A and E – Acute diseases with no chronic phase • Bloodborne transmission – Hepatitis B, C and D – All may produce chronic infections • Agents not associated with disease? – GBV-C (HGV), TTV, SenV Acute Viral Hepatitis (Elevated ALT almost always found) Signs and Symptoms • • • • • • • • • fatigue mild fever loss of appetite flu-like illness (prodromal) muscle/joint aches abdominal pain nausea and vomiting dark urine - light-colored stool yellow eyes and skin (jaundice) Aversion to alcohol and cigarettes Fulminant Viral Hepatitis Acute hepatic failure • Massive hepatic necrosis within 8 weeks of onset • Signs Neurologic - Hepatic Encephalopathy Acute Pancreatitis, jaundice, ascites Coagulopathy - gastrointestinal bleeding Acute Renal Failure - Hepatorenal Syndrome Cardiopulmonary collapse Hepatitis B – Clinical Features • Incubation period: Average 60-90 days Range 45-180 days • Clinical illness (jaundice): <5 yrs, <10% >5 yrs, 30%-50% • Acute case-fatality rate: 0.5%-1% • Chronic infection: <5 yrs, 30%-90% >5 yrs, 2%-10% 2006 HBV: 4,700 Reported Cases 46,000 estimated www.cdc.gov/hepatitis/statistics.htm Chronicity 5% adults MMWR March 21, 2008 / Vol. 57 / No. SS-2 Reported Cases of Acute Hepatitis B in Texas 1980-2005 2500 2000 Hepatitis B recombinant vaccine licensed 1500 1000 500 Universal infant vaccination Universal adolescent vaccination 19 80 19 82 19 84 19 86 19 88 19 90 19 92 19 94 19 96 19 98 20 00 20 02 20 04 0 Reported Risk Characteristics Among Adults HBV Recent (<8 yr ago) Unknown HCV Recent (<15 yr ago) Injection Drug Use Injection Drug Use Sexual Other* MSM Transfusion Heterosexual Unknown Other* With shared risk behaviors integrated testing and prevention makes sense. *Other: Household contact, institutionalization, hemodialysis, occupational exposure etc. Modified from Sentinel Counties Study of Viral Hepatitis, CDC Acute Hepatitis B Incidence By Age and Sex: United States, 2005 0.0 0.0 5-9 0.0 0.0 10-14 0.0 0.0 <5 Female Age Group (Yrs) 15-19 0.6 2.9 35-39 2.9 45-49 50-54 55-59 60+ 2.4 4.3 3.0 30-34 40-44 0.5 1.7 20-24 25-29 Male 4.2 4.5 2.3 4.5 2.2 3.4 1.7 3.0 1.3 0.6 2.2 1.1 Rate per 100,000 Source: National Notifiable Diseases Surveillance System, CDC Acute Hepatitis B Cases by Age Group: Texas, 2005 60+ 50-59 40-49 30-39 20-29 <19 0 10 20 30 Percent of Total Cases 40 Concentration of HBV in Various Body Fluids High Moderate Low/Not Detectable blood semen urine serum vaginal fluid feces wound exudates saliva sweat tears breast milk No Evidence of HBV (or HCV) Transmission • • • • • • Breastmilk Mosquitoes Kissing Food Water Casual contact Chronic Hepatitis: A Syndrome Chronicity – continuing disease, no improvement – greater than 6 months duration Hepatitis - inflammation of the liver – Causes • Viral, drug, toxin, autoimmune, idiopathic – Characterized by necrosis and inflammation • Cirrhosis – end stage liver disease, fibrosis, diffuse parenchymal damage, nodular regeneration Sequelae - 10 to 20 years – Cirrhosis and hepatocellular carcinoma Progression of Liver Disease Time frame: years to decades Fibrosis Cirrhosis BC Hepatitis Services, 2003 Cancer Zeus’s punishment of Prometheus The Golden Fleece and the Heroes Who Lived before Achilles Prometheus Bound For Prometheus to be set free: •An Immortal would have to give up his life for Prometheus – Chiron (centaur) •A mortal would have to slay the liver-eating eagle - Hercules Chronic Hepatitis Burden U.S. • HBV estimated 1.2M persons – 50-70% of these persons born outside U.S. – 2,000-4,000 deaths per year • HCV estimated 3.2-3.7M persons – 70% of these persons age 35-54 years – 8,000-10,000 deaths per year – Elevated ALT, history IDU, and history blood transfusion identified 85% persons 20-59 years • Chronic liver disease and cirrhosis 12th leading cause of death nationally, 6th for Hispanics What proportion of these persons know their sero-status? Sorrell et al, Ann Int Med, 2009 150(2):104, Armstrong et al , Ann Int Med 2006;144(10):705, www.cdc.gov/hepatitis/ Chronic Viral Hepatitis Disease Burden = 409,400 cases Hepatitis B Hepatitis C Prevalence in General Population 5% or 1,115,000 1.6% or 368,000 % Chronic Hepatitis 10% or 115,000 80% or 294,400 Texas 2006 population est. 23 million Chronic Hepatitis B Three Clinical Forms • • • HBeAg Positive Chronic Hepatitis B • • • raised ALT DNA 107 to 1011 copies per ml chronic hepatitis on biopsy HBeAg Negative Chronic Hepatitis B • • • raised ALT DNA 104 to 108 copies per ml chronic hepatitis on biopsy HBsAg Carrier State • • l • Anti-HBe positive normal ALT DNA < 101 to 104 copies per ml minimal nonspecific changes on biopsy Chronic Hepatitis B con’t HBV causes 85% of primary liver cancer worldwide • 20% will develop cirrhosis • 5% will develop hepatocellular cancer HBeAg 10% / yr lose HBeAg - become less (non)infectious – 40% - 50% in 5 years – 70% - 80% in 10 years More frequent in older carriers, associated ALT flare 20% who clear HBeAg have one or more reversions HBsAg 0.5-2% / yr lose HBsAg - become non-carriers Lok ASF, McMahon BJ, Hepatology, 2001;34:1225-1241 McMahon BJ, et al, Ann Intern Med, 2001;135:759-768 Monitoring HBsAg+ Patients • Discuss monitoring with a liver specialist having much experience in managing viral liver diseases. – – – – – Annual physical exam. Blood work every 6-12 mos. Liver biopsy? Liver ultrasound or CT scan every 6-12 mos. fetoprotein (AFP) every 6-12 mos. • Education of patient about disease. Engardio. San Francisco Chronicle, 2003 Hepatitis B: Treatment • Acute hepatitis B – Supportive care • Chronic hepatitis B - HBV DNA/HBeAg clearance (indicator of viral load) Drug Treated patients Controls Interferon-alfa 33%-37% 12%-17% Lamivudine 16%-18% 4%-6% Adefovir Entecavir Telbivudine 12%-14% 21% 23%-26% 6% Hepatitis B: Treatment Costs Drug Interferon-alfa Lamivudine Adefovir Entecavir Monthly $2,084 $449 $900 $811 Annual $26,267 $4,305 $10,705 $9,578 Prevent 500 chronic HBV cases - save $5M annually in Rx Averages based on 2009 wholesale costs, Hepatitis B Foundation, HepB.org • 10% of Asian Americans have chronic HBV versus less than 0.3% of the general population. • Liver cancer second leading cancer for Asian men. • Liver cancer among Asian Americans is 6 to 13 times higher than the general population. HIV HBV Co-infection Multicentre AIDS Cohort Study (MACS) • 5293 men followed • Liver-related mortality: HBV+ 0.8 / 1000 HIV+ 1.7 / 1000 HIV+HBV+ 14.2 / 1000 (p0.001) • Highest mortality rates with lower CD4 nadir counts Thio et al, NEJM 2002;360:1921 Cause of Newly Diagnosed Chronic Liver Disease HBV 4.4% NASH 10% Alcohol 25% Hepatitis C 57% National Cancer Institute – Surveillance Epidemiology and End Results 2006. http://seer.cancer.gov/resources/ Bell et al 2001 HBV Prevalence and Genotype Distribution 1998 F D A A, C, B, D C D B, C B E F F D A A, B,C,D 8% and above = High G, H not determined 2% - 8% = Intermediate Below 2% = Low Global Burden of Hepatitis B Disease • 2 billion with markers of current or past infection • 350 million chronic carriers – 130 million Chinese (1 in 10) have chronic HBV – 15%-25% will die from cirrhosis or liver cancer • 10th leading cause of death – 600,000 to 1 million preventable deaths / year – Second only to tobacco in cause of cancer deaths • Risk of dying from liver cancer 100 greater for carriers than non-carriers Lavanchy D., J Viral Hepat. 2004 Mar;11(2):97-107. WHO. www.who.int/csr/disease/hepatitis/en/ Un homme enceinte s’accouche dans son tombeau* *A pregnant man delivers in his grave Cancer rates, Gambian males 1986-96 Incidence per 100,000 140 120 100 80 all cancer liver cancer 60 40 20 0 014 1519 2024 2529 3034 3539 4044 Age 4549 5054 5559 6064 65+ GHIS Site Review Report 2004 Indonesia: 80–90% home births •Vaccinate all babies within 7 days of birth •70,000 midwives UNIJECT Hepatitis B Carrier Prevalence Before and After Immunization 16 14 12 10 % 8 PRE POST 6 4 2 0 TAIWAN SHANGHAI RURAL CHINA GAMBIA Safe Injection Global Network • ~16 billion injections/year / 12 billion syringes sold ~33% unsafe in developing countries ~12 million HBV infections ~3 million HCV infections ~ 120,000 HIV infections • Estimated 1 billion injections for childhood immunizations • Little change until Global Alliance for Vaccine and Immunizations (GAVI) and SIGN were formed – Eligible countries get auto-disable syringes for 3 years. 200 million already distributed • Countries responsible for national plan, training, waste management Kane A, et al, Bulletin of WHO, 1999, 77:801-807 SIGN Pakistan 2001 SIGN Pakistan 2001 Coalition for Safe Community Needle Disposal 800-643-1648 HBV Childhood Exposure Routes • In Asia, HBV infection is vertical, mother-to-child – 30-40% mothers HBeAg+ • In Africa, horizontal transmission is predominant – About 10% mothers HBeAg+, mothers may be HBsAg- • Studies in two Gambian villages have shown – infection uncommon first year of life – 50% of the children infected by age of 5 – By the age of 10, almost everybody infected, 15 to 20% chronic carriers. • Significant associations, but no predominant route of exposure – Number of siblings – Tropical ulcer scars – E antigen positive household member GHIS Site Review Report 2004 Estimated Births to HBsAg-Positive Mothers United States, 2002 Race/Ethnicity White African American Asian/Pacific Islander Other Total 2002 Births HBsAg Births to HBsAg prevalence (%) positive mothers 3,174,760 (0.13) 4,127 593,691 (0.50) 2,968 210,907 (7.50) 15,818 42,368 (0.50) 212 4,021,726 23,125 Perinatal HBV Transmission Efficacy • If mother positive for HBsAg and HBeAg – 70%-90% of infants infected – 90% of infected infants become chronic carriers • If positive for HBsAg only – 20-30% of infants infected – 90% of infected infants become chronic carriers • In utero transmission rare - accounts for <5% of perinatal infections HBV Vaccine and HBIG • HBIG only ~ 75% effective in preventing carriage – Protection wanes • HBIG & Vaccine ~ 85 – 95% effective • HBV Vaccine only ~ 80 – 90% effective – Birth dose (3-7 days) • HBIG not cost effective developing countries – Little value added Are Three Doses Needed? “Thus, protection against chronic carriage does not depend on the number of doses received as originally assumed…results from GHIS follow-up of vaccinated subjects, more than 95% of children that received at least one dose are protected against the acquisition of chronic carriage early in life.” Fortuin, M. et al Lancet 1993; 341:1129-31 Unapparent exposures as “boosters”? Biologic Processes and Bureaucratic Processes 1 0.9 0.8 0.7 0.6 0.5 Success Failure 0.4 0.3 0.2 0.1 0 1 7 13 19 25 31 37 43 49 55 61 67 73 79 85 91 97 103 109 115 121 127 133 139 145 151 157 163 169 175 181 187 193 199 E f f i c a c y Time Hepatitis B “serum hepatitis” • Hepatitis B virus (1970 Dane particle) - Hepadnaviridae • Enveloped, spherical 42 nm • Partial ds circular DNA genome, about 3.2 kb • Partial + strand, full length - strand, 5’ RT • Four overlapping open reading frames • 9 serotypes, 8 genotypes worldwide – Genotype B milder disease than C • Resistant to environmental stress • 44º C for 7 days, room temperature 6 months, years at -20 º C HBV: Gene Products and Mutants Genome encodes 4 groups of proteins: • C gene - HBcAg (nucleocapsid protein), HBeAg (soluble protein circulates in serum) – ?Associated fulminant hepatitis and severe liver disease – Pre-core mutants lack HBeAg production, 20%-30% US patients • P gene - Polymerase (DNA synthesis) – Associated with resistance to treatment with nucleoside analogs (e.g., lamivudine) • S gene - HBsAg (surface protein) – Concern that these variants may allow replication in the presence of vaccine-induced anti-HBsAg – No evidence to date that variants spread in immunized populations • X gene - X protein (regulates gene transcription) – Associated with hepatocellular carcinoma HBV S-gene mutants •Emergence of HBV variant able to escape the vaccine-induced response suggested in Italy 20 years ago (Zanetti et al, Lancet 1988) •Evidence indicates that amino acid substitution lead to conformational changes which allows mutated HBV to escape vaccine-induced antibodies (G145R) •44 of 1590 (2.8%) vaccinated people, including babies born to HBsAg mothers, became HBV infected despite immunization. All cases showed co-existence of HBsAg and anti-HBs. •At present there is no evidence that S-gene mutants pose a threat to the established PH program of vaccination Hepatitis D Virus • Tiny single stranded RNA virus • A “defective” virus that requires HBVsAg for replication. • Coinfection produces severe disease • Sperinfection often produces chronic disease • Exposure risks same as HBV • Preventing HBV infection prevents HDV infection, why? Hepatitis B Vaccines • Licensed in 1981; currently recombinant (in US) • 3 dose series, 0, 1-2, 4-6 months - no maximum time between doses (no need to repeat missed doses or restart) • 2 dose series (using adult dose) for 11-15 year olds (Merk) • Protection ~50% dose 1; 85% - 2; 96% - 3 Twinrix • Combination adult A and B vaccine • Schedule: 0, 1, 6-12 months • Approved for persons >18 years Recommended for Hepatitis B Vaccination (Adults) • • • • • • • • • • • • High-risk heterosexual men and women MSM Injection drug users Inmates of correctional facilities Health care workers Household and sex partners of persons with chronic infection Hemodialysis patients Recipients of blood products Clients and employees of institution for developmentally disabled Families of adoptees from endemic countries Persons with chronic liver disease Persons who are immunocompromised - HIV Routine vaccine for all children Missed Opportunities for Adult Hepatitis B Vaccination Of all persons with reported acute hepatitis B: • 37% reported prior treatment for an STD • 29% reported prior incarceration • 56% had been treated for an STD and/or incarcerated in a prison or jail prior to their illness Source:Goldstein ST et.al., JID 2002;185:713-9 Improving Hospital Compliance •Problem: Failure to screen mother Failure to give birth dose Failure to give prophylaxis •Root Cause: Too much to do Too many people involved Too complex a process Too few resources??? •Solutions: Put into delivery check-list (simplify) Put into publicly reported quality measures Put development of patient safety culture first Perinatal HBV infections are healthcare-associated infections. Resources • Texas Liver Coalition 800-72-LIVER – www.TexasLiver.org – Affiliated St. Luke’s Episcopal Health System, Houston • Hepatitis – www.LiverFoundation.org – www.TexasDisease.org • HIV and Hepatitis – www.HIVandHepatitis.com – www.numedx.com HBV, HCV and HIV Viruses • Commonalities – Infection through blood and body fluids containing virus – Transmission from mother to child at birth – Produce chronic infections • Differences – Infectivity after sharps injury • HBV 30%, HCV 3%, HIV 0.3% – Level of chronicity • HBV 10% (variable), HCV 75-85%, HIV 100% Other Viruses Associated with Acute Hepatitis Common in U.S.* Exotic** • • • • • • • • Yellow fever • Argentinean hemorrhagic fever • Bolivian hemorrhagic fever • Lassa fever • Rift Valley fever • Marburg • Ebola Cytomegalovirus Epstein-Barr Herpes simplex Varicella zoster Measles Rubella Coxsackie * Each causes less than 1% of acute hepatitis. ** Not usually seen in the U.S.